Mechanisms responsible for the racial disparity in obesity and Type 2 diabetes (T2DM) that are particularly apparent in African-American (AA) women compared to Caucasian women are not understood. While factors such as socioeconomic status and dietary habits likely play a role, emerging data suggests that differences in substrate utilization may contribute to these disparities. Evidence suggests that AA women are metabolically inflexible after an overnight fast, during exercise, or during high fat feeding, and do not increase fat oxidation to levels observed in Caucasian women. Low fat oxidation could result in redirection of lipid into adipose tissue for storage, as well as increased storage of triglyceride and lipotoxic metabolites within skeletal muscle, leading to insulin resistance (IR) and increased risk for development of diabetes. Greater insulin resistance is observed in AA women. These observations in AA compared to Caucasian women are similar to the metabolic inflexibility observed in obese insulin resistant compared to lean individuals. While AA women demonstrate IR, they have lower levels of visceral and hepatic lipid accumulation. This is a paradoxical finding as visceral and hepatic lipid stores are strong risk factors for IR and metabolic diseases. Taken together, the data suggests that IR is phenotypically distinct in AA compared to Caucasian women, and that the lower insulin sensitivity may be due differences in skeletal muscle, leading to peripheral IR. However, we could find no reports comparing hepatic and peripheral insulin sensitivity, and very limited data in AA women for skeletal muscle characteristics that have been demonstrated to be related to insulin resistance in obese and T2DM subjects. Limited data supports a role for increased muscle lipid accumulation in skeletal muscle and insulin resistance in AA women, but we could find no data on lipotoxic lipid levels or mitochondrial content in AA women. Based on these observations, our hypothesis is that inherent differences in skeletal muscle in AA women results in impaired fat oxidation and accumulation of lipid and lipid metabolites within skeletal muscle, and is a link between the development of obesity, insulin resistance and Type 2 diabetes in AA women. To address this hypothesis we have developed 3 Aims: 1) Determine fat oxidation during sub-maximal exercise in AA and Caucasian women;2) Determine lipid accumulation and skeletal muscle characteristics (e.g. muscle fiber type, capillary density, oxidative capacity, mitochondrial content) that have been shown to be related to insulin sensitivity;and 3) Assess insulin sensitivity (peripheral and hepatic), and examine the relationship between insulin sensitivity, fat oxidation and skeletal muscle characteristics. Before we can begin to tease apart environmental and genetic factors that play a role in racial differences in fat oxidation and insulin sensitivity, we need to gain a better understanding of the underlying physiology. The detailed in vivo and ex vivo evaluations we propose using state of the art techniques will provide detailed phenotype information that will provide valuable insight into the increased prevalence of Type II diabetes observed in AA women. PUBLIC HEALTH RELEVANCE: The likelihood of being obese or having diabetes is twice as high in African-American women compared to Caucasian women. Reasons for these health disparities are not understood, but growing evidence suggests that lower fat oxidation in AA women leads to accumulation of fat within skeletal muscle which can lead to the development of insulin resistance and diabetes. Before we can begin to understand the environmental and genetic factors that play a role in racial differences in obesity and diabetes, we need to gain a better understanding of the metabolism and skeletal muscle characteristics related to fat oxidation which may lead to the increased risk of development of metabolic diseases in AA women.